Synthesis and evaluation of alpha,beta-unsaturated alpha-aryl-substituted fosmidomycin analogues as DXR inhibitors

Bioorg Med Chem Lett. 2007 Sep 1;17(17):4920-3. doi: 10.1016/j.bmcl.2007.06.026. Epub 2007 Jun 10.

Abstract

Fosmidomycin, which acts through inhibition of 1-deoxy-D-xylulose phosphate reductoisomerase (DXR) in the non-mevalonate pathway, represents a valuable recent addition to the armamentarium against uncomplicated malaria. In this paper, we describe the synthesis and biological evaluation of E- and Z-alpha,beta-unsaturated alpha-aryl-substituted analogues of FR900098, a fosmidomycin congener, utilizing a Stille or a Suzuki coupling to introduce the aryl group. In contrast with our expectations based on the promising activity earlier observed for several alpha-substituted fosmidomycin analogues, all synthesized analogues exhibited much lower binding affinity for DXR than fosmidomycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacology
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology*
  • Fosfomycin / analogs & derivatives*
  • Fosfomycin / chemical synthesis
  • Fosfomycin / chemistry
  • Inhibitory Concentration 50
  • Malaria / drug therapy*
  • Models, Chemical
  • Molecular Structure
  • Multienzyme Complexes / antagonists & inhibitors*
  • Oxidoreductases / antagonists & inhibitors*
  • Plasmodium falciparum / enzymology
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Enzyme Inhibitors
  • Multienzyme Complexes
  • Fosfomycin
  • fosmidomycin
  • Oxidoreductases
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases